This career development project is focused on studying genetic variations in NADPH Oxidase gene family members (Nox1, Nox4 and p22phox), SODs (SOD1, SOD2 and SOD3) and catalase as melanoma risk factors. This project serves multiple purposes: 1) as a learning platform for me to be trained as a cancer epidemiologist; 2) to test a novel hypothesis on UV-induced, ROS-driven mechanism of melanoma etiology; and 3) to lay out a foundation for my long-term career development on melanoma prevention. My immediate research goal is to understand the role of the Nox pathway genes in melanoma etiology. My long-term career goal is to become an expert in melanoma epidemiology, cancer control and targeted chemoprevention. To achieve these goals will require integrated knowledge and skills in etiology, epidemiology, signal transduction and translational oncology. This project brings together a group of well achieved mentors whose expertise covers epidemiology, statistics and chemoprevention. Dr. Hoda Anton- Culver, an internationally recognized outstanding epidemiologist will be my primary mentor and guide me through studies on epidemiology. Dr. Ziogas (a senior biostatistician) will be my biostatistics mentor. Dr. Meyskens an outstanding and well-achieved cancer prevention expert, who also possess extensive knowledge on melanoma biology, will guide me through studies on UV-induced skin signal transduction and applying the results to translational studies. The key elements of my career development activities include: 1) Didactic training (seminars, conferences, meetings with mentors) and Master of Science studies in Epidemiology; 2) Acquire expertise in epidemiology research; 3) Expand my skills and knowledge in melanoma tumor biology and cancer prevention; 4) Acquire experience in mentoring undergraduate students and teaching. The first aim of this project is to examine the association of previously identified functional SNPs in Nox pathway with melanoma risk in a population-based case-control study (Aim 1A), as well as mechanistic study of how these variants affect the cellular ROS levels, UV-induced DNA damage and NRAS oncogene activation (Aim 1B). Next we will evaluate whether there is an association between germline genetic variants of Nox family genes with NRAS mutations in the tumors (Aim 2). The aims above combine both epidemiologic and mechanistic understanding to study melanoma etiology. This study not only has the potential of a significant impact on melanoma prevention and control, it will also be of preeminent importance to research on other cancer types as ROS has been demonstrated to be associated with the etiology of many cancer types. Furthermore, this grant will give me an excellent opportunity and protected time to establish a successful independent career path as a molecular epidemiologist with strong basic science skills.